University of Illinois scientists have found a way to improve the properties of T-cell receptors -- and potentially other proteins, opening the door to manipulating a virtually untapped part of the immune system to fight autoimmune and viral diseases.
U of Ideas in Science -- June 1999
Contact: Jim Barlow, Life Sciences Editor
Discovery could lead to manipulating part of body's immune system
CHAMPAIGN, Ill. -- University of Illinois scientists have found a way to improve the properties of T-cell receptors -- and potentially other proteins. In doing so, they've opened the door to manipulating a virtually untapped part of the immune system to fight autoimmune and viral diseases.
A team -- led by biochemist David M. Kranz and chemical engineer K. Dane Wittrup -- has discovered that mutations within two regions of the receptor protein allow it to be displayed on the surface of yeast. Their biotechnological breakthrough appeared in the May 11 issue of the Proceedings of the National Academy of Sciences.
The researchers used a yeast-display system, which was created in 1997 in Wittrup's lab, in combination with directed evolution -- a genetic engineering process in which a protein is subjected to random amino- acid changes, and then only those proteins with desired properties are selected. Their selection process also used flow-cytometry equipment at the U. of I. Biotechnology Center.
"T-cells and their T-cell receptors represent one-half of the immune system's capability to recognize infection," Kranz said. "There has not been a method available to engineer these like you can do with antibodies. This paper shows that we've found a way to begin engineering the recognition molecules from the T-cell immune system. Realistically, we're a long way from seeing new therapeutic approaches, but the development of this capability is a major initial step."
Such a strategy may prove beneficial in manipulating the immune system's ability to bind to infected cells. Such binding has been difficult in AIDS and cancer, because infections often remain invisible to antibody-based treatments. Likewise, the researchers said, genetically engineered receptors could be used to block inappropriate immune responses in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
Scientists around the world have been refining monoclonal antibodies -- proteins similar to those that occur naturally in the immune system that search for and bind to specific antigens -- since the 1970s. However, similar refinements to T-cell receptors have not been possible for reasons that were unclear.
The structure of antibodies and T-cell receptors are similar, but the responses of each are carried out very differently. "The immune system looks around for things that don't belong," said Wittrup, the James W. Westwater professor of chemical engineering at the U. of I. "The two major classes of molecules that accomplish this are the recognition proteins -- antibodies and T-cell receptors. We are working at the contact point of where the immune system decides something does or doesn't belong."
The research -- funded by the National Institutes of Health and Whitaker Biomedical Engineering Foundation -- offers the hope of doing genetic engineering directly on recognition molecules from the T-cell system.
"In addition, this strategy for T-cell receptors may be of general use in the study and directed evolution of other proteins that to date have been impossible to improve," Kranz said.